DE10209583B4 - Process for the preparation of 4- (6-bromohexyloxy) -butylbenzene - Google Patents

Abstract

The invention relates to an improved method for producing 4-(6-bromohexyloxy) butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of a base and a phase transfer catalyst. 4-phenylbutanol is metered in a diluent to a mixture consisting of 1,6-dibromohexane, a base, a phase transfer catalyst, and a diluent. Also disclosed is the use of the resulting 4-(6-bromohexyloxy) butylbenzene for producing salmeterol in a previously known manner.

Description

The The present invention relates to a process for the preparation of 4- (6-bromohexyloxy) -butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence a base and a phase transfer catalyst, as well as the use of the thus prepared 4- (6-bromohexyloxy) -butylbenzene for the preparation of salmeterol in a manner known per se.

background the invention

4- (6-bromohexyloxy) -butylbenzene is a valuable intermediate for the manufacture of the active ingredient Salmeterol, which is used as a bronchodilator to treat asthma or chronic bronchitis is used.

After the teaching of the German patent application DE 34 14 752 For example, 4- (6-bromohexyloxy) butylbenzene is prepared by reacting 4-phenylbutanol with 1,6-dibromohexane with a sodium hydride dispersion as the base. For safety reasons, production on an industrial scale using sodium hydride dispersions is hardly feasible.

The European patent application EP 1 132 373 describes a laboratory process for the preparation of 4- (6-bromohexyloxy) -butylbenzene in which a mixture consisting of 4-phenylbutanol, 1,6-dibromohexane, potassium hydroxide and tetrabutylammonium hydrogen sulfate is stirred at room temperature for 20 hours. However, this laboratory method can not be carried out on an industrial scale, since this reaction is highly exothermic, which leads to a strong increase in the reaction temperature, with difficulty stirrable residues and yield-reducing by-products (elimination products) arise.

Of the The present invention is therefore based on the object, a method to show what makes it possible 4- (6-bromohexyloxy) -butylbenzene in good yields on an industrial scale Scale up and the methods known from the prior art to avoid occurring disadvantages.

detailed Description of the invention

Surprisingly has now been found that 4- (6-bromohexyloxy) -butylbenzene in good Yields and on an industrial scale by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of a base and a phase transfer catalyst can be prepared when add 4-phenylbutanol in a diluent to a mixture consisting of 1,6-dibromohexane, a base, a phase transfer catalyst and a diluent adds.

object The invention thus provides a process for the preparation of 4- (6-bromohexyloxy) -butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence a base and a phase transfer catalyst to give 4-phenylbutanol in a diluent to a mixture consisting of 1,6-dibromohexane, a base, a phase transfer catalyst and a diluent dosed.

One Another object of the invention is the use of the after inventive method prepared 4- (6-bromohexyloxy) butylbenzene for the preparation of Salmeterol in a known manner.

• (A) man als Base ein Alkalimetallhydroxid, wie zum Beispiel Lithiumhydroxid, Natriumhydroxid oder Kaliumhydroxid, insbesondere gepulvertes Kaliumhydroxid einsetzt;
• (B) man als Phasentransferkatalysator (PTK) ein Tetraalkylammonium- oder Tetraalkylphosphoniumsalz, wobei die jeweiligen Alkylgruppen gleich oder verschieden sein können, wie zum Beispiel Salze von Tetraoktylammonium, Methyltrioktylammonium, Tetramethylammonium, Tetraethylammonium, Tetrahexylammonium Aliquat 175 (Tributylmethylammonium) oder Aliquat 336 (Methyltrioktylammonium) verwendet. Vorzugsweise ist der PTK ein Tetraalkylammonium Halogenid, ein Tetraalkylammonium Sulfat, ein Tetraalkylammonium Hydrogensulfat, ein Tetraalkylammonium Nitrat oder ein Tetraalkylammonium Phosphat, insbesondere ein Tetraalkylammonium Hydrogensulfat, ganz besonders bevorzugt Tetra-n-butylammonium Hydrogensulfat. Der Begriff „Alkyl" wie er vor- und nachstehend im Bezug auf den Phasentransferkatalysator verwendet wird umfasst geradkettige und verzweigte Alkylgruppen mit 1 bis 8, vorzugsweise 2 bis 6, insbesondere 4 Kohlenstoffatomen. Als bevorzugte Alkylgruppen seien somit die Ethyl-, n-Propyl-, i-Propyl-, n-Butyl-, 2-Butyl, tert-Butyl-, n-Pentyl-, 2-Pentyl-, neo-Pentyl-, n-Hexyl- und 2-Hexylgruppe genannt. Ganz besonders bevorzugt ist die n-Butylgruppe.

Preferred embodiments of the process according to the invention are processes wherein:

• (A) using as the base an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, in particular powdered potassium hydroxide;
• (B) using as phase transfer catalyst (PTK) a tetraalkylammonium or tetraalkylphosphonium salt, the respective alkyl groups being the same or different, for example salts of tetraoctylammonium, methyltrioctylammonium, tetramethylammonium, tetraethylammonium, tetrahexylammonium aliquot 175 (tributylmethylammonium) or aliquat 336 (methyltrioctylammonium) used. Preferably, the PTK is a tetraalkylammonium halide, a tetraalkylammonium sulfate, a tetraalkylammonium hydrogensulfate, a tetraalkylammonium nitrate or a tetraalkylammonium phosphate, especially a tetraalkylammonium hydrogensulfate, most preferably tetra-n-butylammonium hydrogensulfate. The term "alkyl" as used above and below with respect to the phase transfer catalyst comprises straight-chain and branched alkyl groups having 1 to 8, preferably 2 to 6, in particular 4, carbon atoms. , i-propyl, n-butyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, neo-pentyl, n-hexyl and 2-hexyl groups n-butyl group.

• (C) man als Verdünnungsmittel einen aromatischen Kohlenwasserstoff, vorzugsweise Benzol, Toluol oder Xylol, insbesondere Toluol, oder einen gegebenenfalls halogenierten aliphatischen Kohlenwasserstoff, vorzugsweise Dichlormethan, Chloroform, Tetrachlorkohlenstoff oder Dichlorethan, insbesondere Dichlormethan verwendet;
• (D) man die Umsetzung in einem Temperaturbereich von -10 °C bis + 30 °C, vorzugsweise von 0 ° C bis 28 °C, insbesondere von 20 bis 25 °C durchführt;
• (E) man das 4-Phenylbutanol innerhalb von 10 bis 240 Minuten, vorzugsweise 15 bis 60 Minuten zudosiert und die erhaltene Reaktionsmischung noch weitere 30 bis 180, vorzugsweise 45 bis 150 Minuten nachrührt;
• (F) man 0,75 bis 2,5 Äquivalente, vorzugsweise 1,5 bis 2,2 Äquivalente, insbesondere etwa 2 Äquivalente 1,6-Dibromhexan bezogen auf 1 Äquivalent 4-Phenylbutanol einsetzt;
• (G) man 2,5 bis 5,5 Äquivalente, vorzugsweise 2,8 bis 5,2 Äquivalente, insbesondere 3,0 bis 4,0 Äquivalente an Base bezogen auf 1 Äquivalent 4-Phenylbutanol einsetzt;
• (H) man 0,01 bis 0,5 Äquivalente, vorzugsweise 0,02 bis 0,2 Äquivalente, insbesondere 0,05 bis 0,15 Äquivalente an Phasentransferkatalysator bezogen auf 1 Äquivalent 4-Phenylbutanol einsetzt;
• (I) das Gemisch aus 1,6-Dibromhexan, einer Base, einem Phasentransferkatalysator und einem Verdünnungsmittels 1,5 bis 4,0 Volumenteile, vorzugsweise 2,0 bis 3,0 Volumenteile, insbesondere 2,2 bis 2,8 Volumenteile an Verdünnungsmittel bezogen auf ein Volumenteil 1,6-Dibromhexan enthält;
• (J) das Gemisch aus 4-Phenylbutanol und Verdünnungsmittel 1,5 bis 10 Volumenteile, vorzugsweise 2,0 bis 6,0 Volumenteile, insbesondere 3,0 bis 5,0 Volumenteile an Verdünnungsmittel bezogen auf ein Volumenteil 4-Phenylbutanol enthält;
• (K) man nach Beendigung der Umsetzung Wasser zur Reaktionsmischung hinzufügt, die Phasen trennt, die organische Phase mit Wasser wäscht, unter reduziertem Druck einengt und den Rückstand unter Hochvakuum fraktioniert destilliert.

Further preferred embodiments of the method according to the invention are methods in which:

• (C) the diluent is an aromatic hydrocarbon, preferably benzene, toluene or xylene, in particular toluene, or a optionally halogenated aliphatic hydrocarbon, preferably dichloromethane, chloroform, carbon tetrachloride or dichloroethane, especially dichloromethane used;
• (D) carrying out the reaction in a temperature range from -10 ° C to + 30 ° C, preferably from 0 ° C to 28 ° C, in particular from 20 to 25 ° C;
• (E) adding the 4-phenylbutanol within 10 to 240 minutes, preferably 15 to 60 minutes and stirring the resulting reaction mixture for a further 30 to 180, preferably 45 to 150 minutes;
• (F) one uses 0.75 to 2.5 equivalents, preferably 1.5 to 2.2 equivalents, in particular about 2 equivalents of 1,6-dibromohexane based on 1 equivalent of 4-phenylbutanol;
• (G) one uses 2.5 to 5.5 equivalents, preferably 2.8 to 5.2 equivalents, in particular 3.0 to 4.0 equivalents of base based on 1 equivalent of 4-phenylbutanol;
• (H) one uses 0.01 to 0.5 equivalents, preferably 0.02 to 0.2 equivalents, in particular 0.05 to 0.15 equivalents of phase transfer catalyst based on 1 equivalent of 4-phenylbutanol;
• (I) the mixture of 1,6-dibromohexane, a base, a phase transfer catalyst and a diluent 1.5 to 4.0 parts by volume, preferably 2.0 to 3.0 parts by volume, in particular 2.2 to 2.8 parts by volume of diluent contains 1,6-dibromohexane based on one part by volume;
• (J) the mixture of 4-phenylbutanol and diluent contains 1.5 to 10 parts by volume, preferably 2.0 to 6.0 parts by volume, especially 3.0 to 5.0 parts by volume of diluent, relative to one part by volume of 4-phenylbutanol;
• (K) water is added to the reaction mixture after completion of the reaction, the phases are separated, the organic phase is washed with water, concentrated under reduced pressure and the residue is fractionally distilled under high vacuum.

In a particularly preferred embodiment becomes 1 equivalent 4-phenylbutanol in the approximately double volume of toluene within from 10 to 60 minutes to a mixture of about 2 equivalents 1,6-dibromohexane, 3 to 5 equivalents KOH, about 0.1 equivalent Tetra-n-butylammonium hydrogen sulfate and 4 to 6 times the volume to toluene based on the volume of 4-phenylbutanol at a Temperature between 20 and 30 ° C with stirring added. After completion of the addition is rinsed with toluene and 90 to 360, preferably about 180 to 240 minutes at a temperature between 20 and 30 ° C stirred. Subsequently water is added, the organic phase is separated and washed with water. The organic phase is concentrated and the residue fractionally distilled in a high vacuum.

Further advantageous aspects of the procedure according to the invention are the high space-time yield in the present process and the high Yield and purity of 4- (6-bromohexyloxy) -butylbenzene, which be processed directly or after distillation to salmeterol can.

Starting from the 4- (6-bromohexyloxy) -butylbenzene prepared by the process according to the invention, the preparation of salmeterol is carried out in a manner known per se, as described, for example, in US Pat DE 34 14 752 or the EP 1 132 373 ,

The The following examples serve to illustrate examples of procedures carried out for the preparation of 4- (6-bromohexyloxy) -butylbenzene. They are only as possible, To understand exemplary procedures illustrated without the Restrict the invention to its content.

Example 1 4- (6-Bromohexyloxy) -butylbenzene

To a mixture of 509.6 ml (3.3 mol) of 1,6-dibromohexane, 402 g of powdered (6.1 mol KOH) caustic potash, 5.6 g (0.165 mol) of tetra-n-butylammonium hydrogensulfate and 1250 ml of toluene is stirred at a temperature between 20 and 25 ° C with stirring Mixture of 247.5 ml (1.65 mol) of 4-phenylbutanol and 500 ml of toluene dosed within 45 minutes.

To Completion of the addition is rinsed with 125 ml of toluene and 2.5 Stirred at a temperature between 20 and 25 ° C for hours. Then be Added 1875 ml of water, the organic phase is separated and washed twice with 1250 each ml of water. The organic phase is on a rotary evaporator Concentrated under reduced pressure and the residue in a high vacuum (p <0.1 mbar) fractionated distilled. You get 408.5 g (79% of theory) of the title compound as a colorless oil.

Example 2 4- (6-Bromohexyloxy) -butylbenzene

To a mixture of 20.2 ml (0.131 mol) of 1,6-dibromohexane, 16 g of powdered (0.242 mol KOH) of potassium hydroxide, 2.2 g (0.0066 mol) of tetra-n-butylammonium hydrogensulfate and 50 ml Toluene at a temperature between 25 and 30 ° C with stirring a mixture from 10 ml (0.0655 mol) of 4-phenylbutanol and 20 ml of toluene within metered in for 15 minutes.

After completion of the addition is rinsed with 5 ml of toluene and stirred for 2 hours at a temperature between 25 and 30 ° C. subsequently, ßend 75 ml of water are added, the organic phase is separated and washed twice with 50 ml of water. The organic phase is concentrated on a rotary evaporator under reduced pressure and the residue is fractionally distilled under high vacuum (p <0.1 mbar). This gives 14.62 g (71% of theory) of the title compound as a colorless oil.

Comparative Example 1 4- (6-bromohexyloxy) -butylbenzene (corresponding to EP 1 132 373 )

To a mixture of 5 ml (0.0323 mol) of 4-phenylbutanol and 10.1 ml (0.0657 moles) 1,6-dibromohexane, be stirred 8 g of powdered (0.121 mol KOH) of potassium hydroxide added the temperature being about 30 ° C increases. Subsequently 1.1 g (0.0033 mol) of tetra-n-butylammonium hydrogensulfate are added, with the temperature to about 65 ° C increases.

To Completion of the addition is stirred for 20 hours at room temperature. The The reaction mixture is filtered, the filtrate in 50 ml of diethyl ether taken up and mixed with 50 ml of water. The organic phase is separated and dried. The organic phase is on a rotary evaporator Concentrated under reduced pressure and the residue in a high vacuum (p <0.1 mbar) fractionally distilled. You get 5.8 g (56% of theory) of the title compound as a colorless oil.

Comparative Example 2 4- (6-bromohexyloxy) -butylbenzene

To a mixture of 20.2 ml (0.131 mol) of 1,6-dibromohexane, 16 g of powdered (0.242 mol KOH) of potassium hydroxide and 2.2 g (0.0066 mol) of tetra-n-butylammonium hydrogensulfate at a temperature between 20 and 30 ° C with stirring 10 ml (0.0655 mol) of 4-phenylbutanol within metered in for 15 minutes. The reaction was spontaneously exothermic and the temperature was barely controllable. Towards the end of the encore Hard lumps formed and the reaction mixture did not settle stir more.

Claims (15)

A process for preparing 4- (6-bromohexyloxy) -butylbenzene by reacting 4-phenylbutanol with 1,6-dibromohexane in the presence of a base and a phase transfer catalyst, which comprises reacting 4-phenylbutanol in a diluent to give a mixture consisting of 1 , 6-dibromohexane, a base, a phase transfer catalyst and a diluent. Method according to claim 1, characterized in that that used as the base powdered potassium hydroxide. Method according to claim 1 or 2, characterized that as a phase transfer catalyst, a tetraalkylammonium or Tetraalkylphosphoniumsalz used. Method according to claim 3, characterized that is a phase transfer catalyst, a tetraalkylammonium hydrogen sulfate used. Method according to one of claims 1 to 4, characterized that as a diluent an aromatic hydrocarbon or an optionally halogenated aliphatic hydrocarbon used. Method according to claim 5, characterized in that that as a diluent Toluene or dichloromethane used. Method according to one of claims 1 to 6, characterized that the reaction is carried out in a temperature range of -10 ° C to + 30 ° C. Method according to one of claims 1 to 7, characterized that the 4-phenylbutanol is added within 10 to 240 minutes and the resulting reaction mixture for a further 30 to 180 minutes subsequently stirring. Method according to one of claims 1 to 8, characterized characterized in that 0.75 to 2.5 equivalents of 1,6-dibromohexane based on 1 equivalent 4-phenylbutanol starts. Method according to one of claims 1 to 9, characterized that is 2.5 to 5.5 equivalents to base based on 1 equivalent 4-phenylbutanol is used. Method according to one of claims 1 to 10, characterized that is 0.01 to 0.5 equivalents used on phase transfer catalyst based on 1 equivalent of 4-phenylbutanol. Method according to one of claims 1 to 11, characterized that the mixture of 1,6-dibromohexane, a base, a phase transfer catalyst and a diluent 1.5 to 4.0 volumes of diluent based on a part of 1,6-dibromohexane. Method according to one of claims 1 to 12, characterized that the mixture of 4-phenylbutanol and diluent from 1.5 to 10 parts by volume on diluent based on a part of 4-phenylbutanol. Method according to one of claims 1 to 13, characterized in that after Beendi water is added to the reaction mixture, the phases are separated, the organic phase is washed with water, concentrated under reduced pressure and the residue is fractionally distilled under high vacuum. Use of according to one of claims 1 to 14 prepared 4- (6-bromohexyloxy) butylbenzene for the preparation of salmeterol in a conventional manner.